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. 2021 Dec 1;196(6):623-632.
doi: 10.1667/RADE-20-00246.1.

Tomotherapy Applied Total Lymphoid Irradiation and Allogeneic Hematopoietic Cell Transplantation Generates Mixed Chimerism in the Rhesus Macaque Model

Lisa Forrest  1 , John Fechner  2 , Jennifer Post  2 , Nathaniel Van Asselt  1 , Kevin Kvasnica  1   3 , Lynn D Haynes  2 , Jenny Coonen  4 , Kevin Brunner  4 , W John Haynes  2 , Christopher Little  2 , William J Burlingham  2 , Peiman Hematti  5 , Samuel Strober  6 , Dixon B Kaufman  2
Affiliations

Tomotherapy Applied Total Lymphoid Irradiation and Allogeneic Hematopoietic Cell Transplantation Generates Mixed Chimerism in the Rhesus Macaque Model

Lisa Forrest et al. Radiat Res. .

Abstract

Development of a new methodology to induce immunological chimerism after allogeneic hematopoietic cell (HC) transplantation in a rhesus macaque model is described. The chimeric state was achieved using a non-myeloablative, helical tomotherapy-based total lymphoid irradiation (TomoTLI) conditioning regimen followed by donor HC infusions between 1-haplotype matched donor/recipient pairs. The technique was tested as a feasibility study in an experimental group of seven rhesus macaques that received the novel TomoTLI tolerance protocol and HC allo-transplants. Two tomotherapy protocols were compared: TomoTLI (n = 5) and TomoTLI/total-body irradiation (TBI) (n = 2). Five of seven animals developed mixed chimerism. Three of five animals given the TomoTLI protocol generated transient mixed chimerism with no graft-versus-host disease (GVHD) with survival of 33, 152 and >180 days. However, the inclusion of belatacept in addition to a single fraction of TBI resulted in total chimerism and fatal GVHD in both animals, indicating an unacceptable conditioning regimen.

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Figures

FIG. 1.
FIG. 1.
Helical tomotherapy. Panel A: Tomotherapy machine. Panels B and C: Anterior posterior digitally reconstructed radiograph (DRR) of the TLI target (purple contour) with a 4-mm expansion for the PTV (orange contour) of the rhesus macaque. The separate round contour in the left abdomen is the spleen. Lymph nodes irradiated include cervical, mandibular, axillary, mediastinal, para-aortic, inguinal and medial iliac.
FIG. 2.
FIG. 2.
Tolerance induction protocol and maintenance immunosuppression for HC transplantation. Use of TomoTLI (panel A) and TomoTLI/TBI (panel B).
FIG. 3.
FIG. 3.
Peripheral donor cell chimerism. Panel A: Kinetics of chimerism as measured by short tandem repeats in animals H1–4. Panel B: Kinetics of chimerism as measured by flow cytometic methodology in animals H5–7. Panels C–E: Linage chimerism of donor cell subsets in animals H5–7 of T cells (CD45þCD3þ), B cells (CD45þCD20þ) and monocytes (CD45þCD14þHLA-DRþCD11bþ), respectively.
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Comment in

  • Opioid-free Anesthesia: Reply.
    Kharasch ED, Clark JD. Kharasch ED, et al. Anesthesiology. 2021 Oct 1;135(4):759-760. doi: 10.1097/ALN.0000000000003912. Anesthesiology. 2021. PMID: 34388824 Free PMC article. No abstract available.

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